Clinical and molecular analysis in Papillon–Lefèvre syndrome

Abstract

Papillon-Lefèvre syndrome (PLS; MIM#245000) is a rare recessive autosomal disorder characterized by palmar and plantar hyperkeratosis, and aggressively progressing periodontitis leading to premature loss of deciduous and permanent teeth. PLS is caused by loss-of-function mutations in the CTSC gene, which encodes cathepsin C. PLS clinical expressivity is highly variable and no consistent genotype-phenotype correlation has been demonstrated yet. Here we report the clinical and genetic features of five PLS patients presenting a severe periodontal breakdown in primary and permanent dentition, hyperkeratosis over palms and soles, and recurrent sinusitis and/or tonsillitis.Mutation analysis revealed two novel homozygous recessive mutations (c.947T>C and c.1010G>C) and one previous described homozygous recessive mutation (c.901G>A), with parents carrying them in heterozygous, in three families (four patients). The fourth family presented with the CTSC c.628C>T mutation in heterozygous, which was inherited maternally. Patient carrying the CTSC c.628C>T mutation featured classical PLS phenotype, but no PLS clinical characteristics were found in his carrier mother. All mutations were found to affect directly (c.901G>A, c.947T>C, and c.1010G>C) or indirectly (c.628C>T, which induces a premature termination) the heavy chain of the cathepsin C, the region responsible for activation of the lysosomal protease. Together, these findings indicate that both homozygous and heterozygous mutations in the cathepsin C heavy chain domain may lead to classical PLS phenotype, suggesting roles for epistasis or gene-environment interactions on determination of PLS phenotypes. K E Y W O R D Scathepsin C, palmoplantar keratoderma, Papillon-Lefèvre syndrome, periodontitis

Identification of putative genetic modifying factors that influence the development of Papillon–Lefévre or Haim–Munk syndrome phenotypes

“…Identification of the disease‐causing mutations is extremely important for therapy or genetic counselling, but clinical genetics has already reached the limitations of the direct sequencing technology, as it is unable to answer clinically relevant questions such as genotype–phenotype correlations or disease prognosis, or explain the development of different clinical variants in patients carrying the same disease‐causing mutation . This is the case with the two PLS and HMS patients examined here and reported previously by our workgroup . Although the same disease‐causing CTSC mutation was identified in both patients, the causative mutation itself does not explain the striking phenotypic differences between them.…”

“…Both patients were missing all permanent teeth and using a permanent dental prosthesis. In our previous paper, we also reported the results of haplotype analysis, which raised the possibility that these patients are siblings . It was not possible to genotype unaffected relatives …”

“…We recently investigated two Hungarian patients, one with PLS and one with HMS, who nonetheless carry the same homozygous nonsense mutation (c.748C/T; p.Arg250X) of the CTSC gene . As there is currently no explanation for why one mutation can lead to these two different clinical variants (PLS and HMS), we were interested in the identification of phenotype‐modifying genetic factors that could facilitate the understanding of the phenotypic differences between these patients.…”

Oral rehabilitation of Papillon–Lefèvre syndrome patients by dental implants: a systematic review

“…PLS is a rare autosomal recessive disorder with dermal and oral manifestations 4,5 . Mutation in the cathepsin C gene (CTSC), which is localized on chromosome 11q14-q21, in these patients causes the loss of cathepsin C function.…”

“…Cathepsin C plays a role in epithelial differentiation and desquamation 6 . The severity of dermal manifestations, including diffuse hyperkeratosis affecting the palms of the hands and soles of the feet, varies in patients from mild psoriasiform scaly skin to overt hyperkeratosis 4,5 . The soles of the feet are usually affected more than the palms, and the degree of hyperkeratosis may be affected by seasonal changes.…”